Velcicky Juraj, Ngo Estelle, Bauer Matthias R, Meyer Arndt, Schlapbach Achim, Racine Sophie, Orain David, Pflieger Daniel, Teixeira-Fouchard Sylvie, Dubois Celine, Goetz Alban, Steiner Roland, Palmieri Marco, Bussenault Alex, Stringer Rowan, Larger Patrice, Riek Simone, Schmutz Patrick, Lehmann Sylvie, Scheufler Clemens, Rondeau Jean-Michel, Burkhart Christoph, Knoepfel Thomas, Gommermann Nina
Novartis Biomedical Research, Novartis Campus, 4056, Basel, Switzerland.
ChemMedChem. 2025 Apr 1;20(7):e202400851. doi: 10.1002/cmdc.202400851. Epub 2025 Jan 12.
The pro-inflammatory cytokine interleukin-17A (IL-17) plays an important role in the body's defense against bacterial and fungal infections. However, overexpression of IL-17 has been associated with several diseases, including rheumatoid arthritis, asthma, psoriasis, and even cancer. The role of IL-17 in psoriasis has been confirmed by clinical use of IL-17 antibodies, e. g. secukinumab (Cosentyx). Ongoing research is focused on discovering low molecular weight IL-17 inhibitors. In this publication, we present thiazole-based IL-17 inhibitors discovered through a scaffold-morphing strategy. This strategy involved ring-opening of a known scaffold and utilization of a chalcogen interaction between thiazole-sulfur and central amide-oxygen to maintain the coplanar conformation found in the parent compound. The new scaffold enabled the generation of highly potent compounds with good overall profile. The optimized compounds 11 and 15 demonstrated good exposure in rats after oral dosing. Importantly, compound 11 exhibited no adverse effects in a rat tolerability study after a four-day administration of up to 300 mg/kg/day.
